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Pokonsolidacyjna terapia kwasem retinowym chorych na agresywną postać nerwiaka zarodkowego (neuroblastoma), leczonych autologicznym przeszczepem hematopoetycznych komórek macierzystych

Información

DOI:
https://doi.org/10.1002/14651858.CD010685.pub3Copiar DOI
Base de datos:
  1. Cochrane Database of Systematic Reviews
Versión publicada:
  1. 25 agosto 2017see what's new
Tipo:
  1. Intervention
Etapa:
  1. Review
Grupo Editorial Cochrane:
  1. Grupo Cochrane de Cáncer infantil

Copyright:
  1. Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Contraer

Autores

  • Frank Peinemann

    Correspondencia a: Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Cologne, Germany

    [email protected]

  • Elvira C van Dalen

    Department of Paediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, Netherlands

  • Heike Enk

    c/o Cochrane Childhood Cancer, Amsterdam, Netherlands

  • Frank Berthold

    Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Cologne, Germany

Contributions of authors

All review authors approved the final version of the review.

FP: concept, selecting and appraising studies (both for the original version of the review and the update), extracting and analysing data, interpretation of results, primary manuscript preparation.

ECVD: appraising studies (for the original version), extracting and analysing data, interpretation of results, manuscript review.

HE: selecting and appraising studies (for the update), manuscript review.

FB: selecting and appraising studies (for the original version), providing a clinical perspective, interpretation of results, manuscript review.

Sources of support

Internal sources

  • University of Cologne, Germany.

    Provision of the full‐text articles

External sources

  • Stichting Kinderen Kankervrij (KiKa), Netherlands.

    The salary of ECVD is paid by KiKa; KiKa was not involved in the design and execution of this Cochrane Review.

Declarations of interest

FP: none known

ECVD: none known

HE: none known

FB: none known

Acknowledgements

We would like to acknowledge the Editorial Base of Cochrane Childhood Cancer for their advice and support. The editorial base of Cochrane Childhood Cancer is funded by Stichting Kinderen Kankervrij (KiKa). We thank Jan Kohler for a timely and appropriate response to an inquiry.

Version history

Published

Title

Stage

Authors

Version

2017 Aug 25

Retinoic acid postconsolidation therapy for high‐risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation

Review

Frank Peinemann, Elvira C van Dalen, Heike Enk, Frank Berthold

https://doi.org/10.1002/14651858.CD010685.pub3

2015 Jan 29

Retinoic acid post consolidation therapy for high‐risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation

Review

Frank Peinemann, Elvira C van Dalen, Doreen A Kahangire, Frank Berthold

https://doi.org/10.1002/14651858.CD010685.pub2

2013 Jul 31

Retinoic acid post consolidation therapy for high‐risk neuroblastoma

Protocol

Frank Peinemann, Carmen Bartel, Ulrich Grouven, Frank Berthold

https://doi.org/10.1002/14651858.CD010685

Differences between protocol and review

In the protocol, we stated that we would present five outcomes in the 'Summary of findings' table: overall survival, treatment‐related mortality, early toxicity, late toxicity, and health‐related quality of life. In the 'Summary of findings' table, up to seven outcomes may be chosen for inclusion that should represent the most important outcomes to patients. Progression‐free survival and event‐free survival lead the list of genuinely important secondary outcomes in the protocol. We added those two outcomes to the 'Summary of findings' table to present more completely the seven most important outcomes. The types of primary and secondary outcomes in the review remain unchanged from the protocol.

Differences between the previous version and this version of the review

The search terms for the ongoing trials database ClinicalTrials.gov have been slightly changed. We specified the search to find study types 'interventional studies' and clinical study phase '2' or '3' to improve precision. In the protocol, we stated that we would search for abstracts presented at the last five consecutive annual meetings of the American Society of Clinical Oncology (ASCO), the International Society of Paediatric Oncology (SIOP) and the Advances in Neuroblastoma Research (ANR). We did not do this for the original version of the review, but did so during the update for ASCO, SIOP, and the meetings of the American Society of Hematology (ASH), but not for ANR.

Keywords

MeSH

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

1Study flow diagram of current review version.Abbreviations. CT.gov: ClinicalTrials.gov; ICTRP: International Clinical Trials Registry Platform
Figuras y tablas -
Figure 1

1Study flow diagram of current review version.

Abbreviations. CT.gov: ClinicalTrials.gov; ICTRP: International Clinical Trials Registry Platform

Flow of patients in the Matthay 1999 study (as prepared by review author FP).
 Abbreviations. BMT: bone marrow transplantation; ContCT: continuation chemotherapy; CT: chemotherapy; HDCT: high‐dose chemotherapy; RA: retinoic acid.
Figuras y tablas -
Figure 2

Flow of patients in the Matthay 1999 study (as prepared by review author FP).
Abbreviations. BMT: bone marrow transplantation; ContCT: continuation chemotherapy; CT: chemotherapy; HDCT: high‐dose chemotherapy; RA: retinoic acid.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 4

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.1 Overall survival.
 Abbreviations. CI: confidence interval; IV: inverse variance; SE: standard error.
Figuras y tablas -
Figure 5

Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.1 Overall survival.
Abbreviations. CI: confidence interval; IV: inverse variance; SE: standard error.

Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.2 Event‐free survival.
 CI: confidence interval; IV: inverse variance; SE: standard error.
Figuras y tablas -
Figure 6

Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.2 Event‐free survival.
CI: confidence interval; IV: inverse variance; SE: standard error.

Comparison 1 Retinoic acid versus no further therapy, Outcome 1 Overall survival.
Figuras y tablas -
Analysis 1.1

Comparison 1 Retinoic acid versus no further therapy, Outcome 1 Overall survival.

Comparison 1 Retinoic acid versus no further therapy, Outcome 2 Event‐free survival.
Figuras y tablas -
Analysis 1.2

Comparison 1 Retinoic acid versus no further therapy, Outcome 2 Event‐free survival.

Summary of findings for the main comparison. Retinoic acid postconsolidation therapy compared to no further treatment for high‐risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation

Retinoic acid postconsolidation therapy compared to no further treatment for high‐risk neuroblastoma patients treated with autologous HSCT

Patient or population: high‐risk neuroblastoma patients treated with autologous HSCT
Settings: paediatric oncology departments
Intervention: retinoic acid postconsolidation therapy
Comparison: no further treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

No further treatment

Retinoic acid post‐consolidation therapy

Overall survival (reported as mortality)

583 per 10001

533 per 1000
(331 to 760)

HR 0.87
(0.46 to 1.63)

98
(1 study)

⊕⊕⊝⊝
low2,3

The length of follow‐up was not mentioned for the 98 participants eligible for this review

Treatment‐related mortality ‐ not reported

See comment

See comment

Not estimable

See comment

No adequate information on this outcome was provided

Progression‐free survival ‐ not reported

See comment

See comment

Not estimable

See comment

No information on this outcome was provided

Event‐free survival (reported as relapse, disease progression, death from any cause, or second neoplasm)

604 per 10001

549 per 1000
(371 to 749)

HR 0.86
(0.50 to 1.49)

98
(1 study)

⊕⊕⊝⊝
low2,3

The length of follow‐up was not mentioned for the 98 participants eligible for this review

Early toxicity ‐ not reported

See comment

See comment

Not estimable

See comment

No adequate information on this outcome was provided

Late toxicity including secondary malignancies ‐ not reported

See comment

See comment

Not estimable

See comment

No adequate information on this outcome was provided

Health‐related quality of life ‐ not reported

See comment

See comment

Not estimable

See comment

No information on this outcome was provided

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; HR: Hazard ratio; HSCT: haematopoietic stem cell transplantation

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1The assumed risk is based on the number of events in the control group at the final time point of the survival curve presented in the included study.
2The presence of selection bias, performance bias, attrition bias and other bias was unclear, so we downgraded one level for study limitations.
3Since this is a small study and the 95% CIs include values favouring both the intervention and the control treatment we downgraded one level for imprecision.

Figuras y tablas -
Summary of findings for the main comparison. Retinoic acid postconsolidation therapy compared to no further treatment for high‐risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation
Table 1. The INRG consensus pretreatment classification scheme

INRG stage

Age (months)

Histologic category

Grade of tumour differentiation

MYCN

11q aberration

Ploidy

Pretreatment risk group

Code

Interpretation

L1/L2

Ganglioneuroma maturing; ganglioneuroblastoma intermixed

A

Very low

L1

Any, except ganglioneuroma or ganglioneuroblastoma

Not amplified

B

Very low

Amplified

K

High

L2

< 18

Any, except ganglioneuroma or ganglioneuroblastoma

Not amplified

No

D

Low

Yes

G

Intermediate

≥ 18

Ganglioneuroblastoma nodular; neuroblastoma

Differentiating

Not amplified

No

E

Low

Yes

H

Intermediate

Poorly differentiated or undifferentiated

Not amplified

H

Intermediate

Amplified

N

High

M

< 18

Not amplified

Hyperdiploid

F

Low

< 12

Not amplified

Diploid

I

Intermediate

12 to < 18

Not amplified

Diploid

J

Intermediate

< 18

Amplified

O

High

≥ 18

P

High

MS

< 18

Not amplified

No

C

Very low

Yes

Q

High

Amplified

R

High

Reference: Cohn 2009.

The INRG consensus classification schema includes the criteria INRG stage, age, histologic category, grade of tumour differentiation, MYCN status, presence/absence of 11q aberrations, and tumour cell ploidy. Sixteen statistically or clinically different pretreatment groups of patients (lettered A through R), or both, were identified using these criteria. The categories were designated as very low (A, B, C), low (D, E, F), intermediate (G, H, I, J), or high (K, N, O, P, Q, R) pretreatment risk subsets.

Figuras y tablas -
Table 1. The INRG consensus pretreatment classification scheme
Table 2. The International Neuroblastoma Staging System

Stage

Definition

1

Localised tumour with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumour microscopically (nodes attached to and removed with the primary tumour may be positive)

2A

Localised tumour with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumour microscopically

2B

Localised tumour with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumour. Enlarged contralateral lymph nodes must be negative microscopically

3

Unresectable unilateral tumour infiltrating across the midlinea, with or without regional lymph node involvement; or localised unilateral tumour with contralateral regional lymph node involvement; or midline tumour with bilateral extension by infiltration (unresectable) or by lymph node involvement

4

Any primary tumour with dissemination to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs (except as defined for stage 4S)

4S

Localised primary tumour (as defined for stage 1, 2A or 2B), with dissemination limited to skin, liver, and/or bone marrowb (limited to infants < 1 year of age)

Reference: Brodeur 1993.

Note: Multifocal primary tumours leg, bilateral adrenal primary tumours should be staged according to the greatest extent of disease, as defined above, and followed by a subscript letter M e.g. 3M.
aThe midline is defined as the vertebral column. Tumours originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.
bMarrow involvement in stage 4S should be minimal, i.e. < 10% of total nucleated cells identified as malignant on bone marrow biopsy or on marrow aspirate. More extensive marrow involvement would be considered to be stage 4. The (Meta‐iodobenzylguanidine) MIBG scan (if performed) should be negative in the marrow.

Figuras y tablas -
Table 2. The International Neuroblastoma Staging System
Table 3. Response to treatment

Response

Primary tumour

Metastatic sites

Complete response

No tumour

No tumour; catecholamines normal

Very good partial response

Decreased by 90% to 99%

No tumour; catecholamines normal; residual 99Tc bone changes allowed

Partial response

Decreased by more than 50%

All measurable sites decreased by > 50%. Bones and bone marrow: number of positive bone sites decreased by > 50%; no more than 1 positive bone marrow site allowed

Minimal response

No new lesions; > 50% reduction of any measurable lesion (primary or metastases) with < 50% reduction in any other; < 25% increase in any existing lesion

No response

No new lesions; < 50% reduction but < 25% increase in any existing lesion

Progressive disease

Any new lesion; increase of any measurable lesion by > 25%; previous negative marrow positive for tumour

Reference: Brodeur 1993.

Figuras y tablas -
Table 3. Response to treatment
Table 4. Children's Oncology Group assignment to low, intermediate, and high‐risk group

INSS stage

Age

MYCN

INPC classification

DNA index

Risk group

1

0 to 21 y

Any

Any

Any

Low

2A/2B

< 365 d

Any

Any

Any

Low

≥ 365 d to 21 y

Nonamplified

Any

Low

≥ 365 d to 21 y

Amplified

Favorable

Low

≥ 365 d to 21 y

Amplified

Unfavorable

High

3

< 365 d

Nonamplified

Any

Any

Intermediate

< 365 d

Amplified

Any

Any

High

≥ 365 d to 21 y

Nonamplified

Favorable

Intermediate

≥ 365 d to 21 y

Nonamplified

Unfavorable

High

≥ 365 d to 21 y

Amplified

Any

High

4

< 548 d

Nonamplified

Any

Any

Intermediate

< 365 d

Amplified

Any

Any

High

≥ 548 d to 21 y

Any

Any

High

4S

< 365 d

Nonamplified

Favorable

> 1

Low

< 365 d

Nonamplified

Any

= 1

Intermediate

< 365 d

Nonamplified

Unfavorable

Any

Intermediate

< 365 d

Amplified

Any

Any

High

Reference: NCI PDQ 2017
DNA index: favorable > 1 (hyperdiploid) or < 1 (hypodiploid); unfavorable = 1 (diploid).
Abbreviations. d: days of age; y: years of age.

Figuras y tablas -
Table 4. Children's Oncology Group assignment to low, intermediate, and high‐risk group
Table 5. Toxicity possibly associated with retinoic acid after high‐dose chemotherapy followed by autologous haematopoietic stem cell transplantation

Study

Study design

Type of HSCT

Type of RA

Dose1

Pat2

Type of adverse event (N of affected participants)

Clarke 2003

CR

PBSCT

CRA

160

1

Pneumocystis carinii pneumonia (1)

Cross 2009

CR

NR

CRA

160

1

Hypercalcaemia (1), osteoblastic lesions (1)

De Kraker 2008

SA‐IS

BMT or PBSCT

CRA

160

44

NR

Granger 2012

SA‐IS

PBSCT

CRA

160

33

NR

Hamidieh 2012

SA‐IS

PBSCT

CRA

120 to 160

14

NR

Haysom 2005

CR

BMT

CRA

160

2

Bone marrow transplant nephropathy (2)

Inamo 1999

CR

BMT

CRA

33 to 1023

1

Growth failure (1)

Khan 1996

SA‐IS

BMT

CRA

100 to 200

31

Grade 3/4 toxicity of skin, liver and hypercalcaemia correlated with peak serum levels of CRA

Kletzel 2002

SA‐IS

PBSCT

CRA

160

12

Ataxia (1)

Kogner 2004

RCT

BMT

CRA

NR

12

NR

Kohler 2000

RCT

NR

CRA

15 to 224

NR

Dry skin (47), cheilitis (24), bone pain (16), other (13)

Kreissman 2013

RCT

PBSCT

CRA

160

192

Grade 3 toxic effects: hypertension (4), hematuria (2), elevated serum creatinine (2), proteinuria (3); purged and non‐purged transplantation group combined

Kushner 2003a

CS

NR

CRA

160

1

Cheilitis (1)

Laskin 2011

CS

NR

CRA

NR

20

NR

Marabelle 2009

CR

NR

CRA

160

3

Hypercalcaemia (3)

Marmor 2008

CR

NR

Fenretinide

666 to 20515

2

Rod electroretinogram suppression (2)

Mastrangelo 2011

SA‐IS

PBSCT

CRA

160

8

NR

Matthay 2006

SA‐IS

BMT

CRA

160

22

NR

Mugishima 2008

CR

BMT

CRA

130 to 400

2

Hypercalcaemia (2)

Nishimura 1997

CR

BMT

CRA

33 to 1023

1

Generalised metaphyseal modification (1)

Park 2011

SA‐IS

PBSCT

CRA

160

30

NR

Rayburg 2009

CR

NR

Fenretinide

2210

1

Langerhans cell histiocytosis (1)

Saarinen‐Pihkala 2012

SA‐IS

BMT or PBSCT

CRA

NR

36

NR

Simon 2011

SA‐IS

NR

CRA

160

75

NR

Sirachainan 2008

CR

NR

CRA

140

1

NR

Sung 2007

SA‐IS

PBSCT

CRA

125

44

Skin eruption, particularly face

Turman 1999

CR

BMT

CRA

160

2

Bone marrow transplant nephropathy (2)

Veal 2007

SA‐IS

NR

CRA

160

28

Mild skin toxicity (9), cheilitis (1), hypercalcaemia (2)

Veal 2013

SA‐IS

NR

CRA

160

103

Grade 3 ‐ 4 skin toxicity or cheilitis (5)

Villablanca 1993

SA‐IS

BMT

CRA

100 to 200

49

Dose‐limiting toxicity of hypercalcaemia (3), arthralgia and myalgia (1), grade 1 to 3 hypercalcaemia (9)

Villablanca 1995

SA‐IS

BMT

CRA

200

51

Hypercalcaemia (3), rash (2)

Villablanca 2011

SA‐IS

NR

Fenretinide

1800 to 2475

626

Rash (1), diarrhoea (1), nausea (2), vomiting (1), nyktalopia (1), abdominal pain (4)

Yu 2010

RCT

NR

CRA

160

108

"Few toxic effects"

Notice: Studies presented in this table were not eligible for inclusion in this review.

1Dose in mg/m2/day. The unit mg/kg may be transformed to mg/m2. The average body weight, body length, and body surface of a 6‐month‐old child may be 8 kg, 67 cm, and 0.39 m2, thus 8 kg divided by 0.39 m2 is roughly equalto a conversion factor of 20 (CDC 2000a). This factor increases continuously with age. The average body weight, body length, body surface of an 11‐year‐old child may be 36 kg, 143 cm, and 1.20 m2, thus 36 kg divided by 1.20 m2 is roughly equal to a conversion factor of 30 (CDC 2000b). The unit mg per day may be transformed to m2 per day. For example, 300 mg per day may vary on average between 769 mg/m2 (300 mg/0.39 m2) and 250 m2 (300 mg/1.20 m2)

2Participants treated with retinoic acid after HDCT followed by autologous HSCT acid and evaluated for toxicity.

3Inamo 1999; Nishimura 1997: Patients received retinoic acid at a dose of 40 mg per day. The daily dose may vary on average between 102 mg/m2 (40 mg/0.39 m2) and 33 m2 (40 mg/1.20 m2)

4Kohler 2000: Participants received retinoic acid at a dose of 0.75 mg/kg per day. The daily dose may vary on average between 15 mg/m2 (0.75 mg/kg * 20) and 22 mg/m2 (0.75 mg/kg * 30).

5Marmor 2008: Participants received retinoic acid at a dose of 800 mg per day. The daily dose may vary on average between 2051 mg/m2 (800 mg/0.39 m2) and 666 m2 (800 mg/1.20 m2).

6Villablanca 2011: 51 of the 62 participants received HSCT.

BMT: bone marrow transplantation; CR: case report; CS: case series; CRA: 13‐cis‐retinoic acid; HDCT: high‐dose chemotherapy; HSCT: haematopoietic stem cell transplantation; N: number of participants; NR: not reported; PBSCT: peripheral blood stem cell transplantation; RA: retinoic acid; SA‐IS: single‐arm intervention study such as phase‐1 or phase‐2 clinical trial

Figuras y tablas -
Table 5. Toxicity possibly associated with retinoic acid after high‐dose chemotherapy followed by autologous haematopoietic stem cell transplantation
Comparison 1. Retinoic acid versus no further therapy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

1

Hazard Ratio (Random, 95% CI)

0.87 [0.46, 1.63]

2 Event‐free survival Show forest plot

1

Hazard Ratio (Random, 95% CI)

0.86 [0.50, 1.49]

Figuras y tablas -
Comparison 1. Retinoic acid versus no further therapy